Compounds that block sodium channels in the membranes of cardiac or neuronal tissues are known. For example, Class I antiarrhythmic compounds, such as lidocaine, will block membrane channels for sodium ions in cardiac tissue. A subset of such antiarrhythmic compounds (known as Class Ia antiarrhythmics) includes quinidine and procainamide which are capable of blocking potassium channels in cardiac tissue in addition to blocking sodium channels. Such antiarrhythmic compounds will also block sodium channels in neuronal tissue which is a property of a local anaesthetic compound.
Class I antiarrhythmic compounds may be used to treat supraventricular arrhythmias and ventricular arrhythmias. Treatment of ventricular arrhythmia is very important since such an arrhythmia, especially ventricular fibrillation, can be fatal. Serious ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) occur most often in the presence of myocardial ischemia and/or infarction. Ventricular fibrillation often occurs in the setting of acute myocardial ischemia, before infarction fully develops. At present, lidocaine is the current drug of choice for prevention of ventricular fibrillation. However, many Class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction. Therefore, there is a need in the art to identify new antiarrhythmic treatments, particularly treatments for ventricular arrhythmias. The present invention fills the need, and further provides other related advantages.
It has been suggested that opioid antagonists, such as naloxone or opioid agonists, may interact with sodium channels and have antiarrhythmic activity. However, the opioid activity is probably separate from any such antiarrhythmic activity, as the former activity appears to be stereospecific but the latter activity is not (Sarne, Y., et al. (1991) Brit. J. Pharmacol., 102:696-698).
International patent application WO 86/07257 published Dec. 18, 1986, suggested an antiarrhythmic utility for certain aminocycloalkylamide compounds previously known to be analgesics. One such compound is known as U-50,488H and has been shown to be an opioid agonist particularly active at the kappa receptor (Von Voightlander, P. F., et al. (1983) J. Pharmacol. Exp. Ther., 244:7-12). It has also been suggested that U-50,488H may have a local anaesthetic activity by reducing sodium conductance (Alzheimer, C. and Ten Bruggencate, G. (1990) J. Pharmacol. Exp. Ther., 255:900-905). The analgesic and local anaesthetic properties of U-50,488H are antagonized by the kappa opioid antagonist, naloxone. However, other researchers have been unable to demonstrate any significant antiarrhythmic activity of U-50,488H (Sitsapesan, R., and Parratt, J. R. (1989) Br. J. Pharmacol., 97:795-800) and, it has been predicted that U-50,488H is actually arrhythmogenic (Wong, T. M., et al. (1990) J. Mol. Cell Cardiol., 22:1167-1175).
A different group of analgesic aminocyclohexylamide compounds are described in Horwell's U.S. Pat. Nos. 4,579,863; 4,598,087; 4,656,182; 4,663,343; 4,737,493; and 4,855,316. The opioid activity of these compounds is antagonized by naloxone and is stereospecific with respect to the enantiomers at the amine and amide substituents of the cyclohexyl ring (see: Meecham, K. G., et al. (1989) Eur. J. Pharmacol., 73:151-157; Singh, L. et al. (1990) Eur. J. Pharmacol., 191:477-480; and Hunter, J. C., et al. (1990) Br. J. pharmacol., 101:183-189).